2. Academic Validation
  3. M6A demethylase FTO-mediated downregulation of DACT1 mRNA stability promotes Wnt signaling to facilitate osteosarcoma progression

M6A demethylase FTO-mediated downregulation of DACT1 mRNA stability promotes Wnt signaling to facilitate osteosarcoma progression

  • Oncogene. 2022 Mar;41(12):1727-1741. doi: 10.1038/s41388-022-02214-z.
Dongming Lv  # 1 2,  Shirong Ding  # 3,  Li Zhong 4 5,  Jian Tu 1 2,  Hongbo Li 1 2,  Hao Yao 1 2,  Yutong Zou 1 2,  Ziliang Zeng 1 2,  Yan Liao 1 2,  Xuesi Wan 6,  Lili Wen 7,  Xianbiao Xie 8 9
Affiliations

Affiliations

  • 1 Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 2 Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, China.
  • 3 Department of Radiation Oncology, Sun Yat-sen University Cancer Centre, Guangzhou, China.
  • 4 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 5 Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
  • 6 Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 7 Department of Anesthesiology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. wenll@sysucc.org.cn.
  • 8 Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. xiexbiao@mail.sysu.edu.cn.
  • 9 Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, China. xiexbiao@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 35121825 DOI: 10.1038/s41388-022-02214-z
Abstract

Despite advances in clinical diagnosis and treatment, the prognosis of patients with osteosarcoma (OS) remains poor, and the treatment efficacy has plateaued. Therefore, it is important to identify new therapeutic targets for OS. N6-methyladenosine (m6A) modification has been reported to participate in tumor malignancy. In this study, functional screening showed that the m6A demethylase FTO could be a candidate therapeutic target for OS. Upregulated FTO in OS could predict a poorer prognosis. FTO promoted the growth and metastasis of OS in vitro and in vivo. Methylated RNA immunoprecipitation Sequencing (MeRIP-seq) and RNA Sequencing (RNA-seq) were performed to identify DACT1 as a potential target of FTO. In vitro assays demonstrated that FTO could reduce the mRNA stability of DACT1 via m6A demethylation, which decreased DACT1 expression and further activated the Wnt signaling pathway. The oncogenic effect of FTO on OS was dependent on DACT1. In addition, the m6A reader IGF2BP1 was validated to participate in the regulation of DACT1. Entacapone, a conventional drug for Parkinson's disease, was confirmed to suppress OS via m6A-mediated regulation through the FTO/DACT1 axis. Our findings demonstrate that FTO may be a novel therapeutic target and that entacapone has preclinical value to be repurposed for OS.

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